Distal Myopathy

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Copyright 2007

NORD is very grateful to Professor Nigel G. Laing, NH & MRC Principal Research Fellow, Centre for Medical Research, University of Western Australia, West Australian Institute for Medical Research, for assistance in the preparation of this report.

Synonyms of Distal Myopathy

Distal Muscular Dystrophy

Disorder Subdivisions

Distal Myopathy 3 (MPD3)

Distal Myopathy with Rimmed Vacuoles (DMRV)

Distal Myopathy with Vocal Cord and Pharyngeal Signs

Inclusion Body Myopathy Type 2 (IBM2)

Laing Distal Myopathy

Laing Early-Onset Distal Myopathy

Miyoshi Myopathy

Nonaka Myopathy

Tibial Distal Myopathy

Udd Distal Myopathy

Welander Distal Myopathy

General Discussion

Distal myopathy (or distal muscular dystrophy) is a general term for a group of rare progressive genetic disorders characterized by wasting (atrophy) and weakness of the voluntary distal muscles. The distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet. Conversely, the proximal muscles are the muscles closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Although age of onset can occur anytime from infancy to adulthood, most forms develop later in life and are slowly progressive. Inheritance is autosomal dominant or recessive.

The distal myopathies belong to a larger group of disorders known as the muscular dystrophies. The muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns.

Symptoms

The severity, specific symptoms, and progression of the distal myopathies vary greatly, even among members of the same family. Slowly progressive weakness and degeneration of the voluntary distal muscles characterizes these disorders. In some cases, additional muscles including various proximal muscles may become involved.

Welander Distal Myopathy
Most cases of this form of distal myopathy occur in individuals greater than 40 years of age. Certain muscles of the hands and feet (intrinsic muscles and long extensors) and certain muscles of the fingers and toes (extensors) are predominantly affected. Muscle weakness and degeneration ranges from mild to severe. The progression of muscle weakness is slow. Muscles in the hands are affected first with the muscles in the legs becoming involved later on or not at all. Welander distal myopathy has been identified with greater frequency in Sweden and Finland.

Udd Distal Myopathy (Tibial Distal Myopathy)
This form of distal myopathy is characterized by muscle weakness affecting the ankles that may spread to affect the muscles of the shinbone (tibia). Onset is usually after 35 years of age and progression is slow. Eventually the long extensors of the toes may become involved resulting in clumsiness and an inability to turn the feet and toes upward (foot drop), which may make it difficult to pick up the front of the foot when walking. In most cases, Udd distal myopathy only affects the lower limbs. By the mid seventies, some individuals may have involvement of the upper legs muscles (proximal muscles) and may experience mild to moderate difficulty walking.

Laing Distal Myopathy (Laing Early-Onset Distal Myopathy; Distal Myopathy 1; MPD1)
In most cases, Laing distal myopathy onset occurs before the age of 5 and has a distinct pattern of muscle weakness and degeneration. Initially, specific muscles of the ankles and great toes are affected. Muscles of the fingers may also be affected with the third and fourth fingers affected most severely. Additional findings may occur including weakness of neck flexion and mild weakness of certain facial muscles.

In some cases, onset of Laing distal myopathy may be early enough to cause delays in walking in affected infants. In other cases, no symptoms are apparent until the twenties. Approximately 10 years after the onset of distal muscle weakness, the proximal muscles may become mildly affected. Progression of Laing distal myopathy is extremely slow and no affected individuals have required a wheelchair even into their sixties.

Inclusion body myopathy type 2 (IBM2) is characterized by progressive weakness and degeneration of the distal muscles of the legs. Onset ranges from 10 to 40 years of age, but is most common in the late teens to early twenties. Affected individuals may experience gait disturbances and foot drop. Muscle weakness eventually spreads to affect the hands and certain proximal muscles of the upper legs including the thigh and hamstrings. Approximately 20 years after the onset of IBM2, some affected individuals may eventually require a wheelchair.

The muscles of the shoulders and neck may become involved in some case. In rare cases, weakness of certain facial muscles may occur.

Miyoshi Myopathy
Onset of this form of distal myopathy is usually between 15-30 years of age. Affected individuals experience weakness and degeneration of the leg muscles, including the calves, which at first may appear bulky or abnormally large (pseudohypertrophy). Two muscles found in the calf, the gastrocnemius and soleus, are most often first affected by Miyoshi myopathy. Initially, affected individuals may be unable to stand on their toes. Eventually, muscle weakness spreads to affect the proximal muscles of the upper legs often causing difficulties climbing stairs, standing or walking. Muscles in the hands, forearms, and shoulder area may also become affected. As the disease progresses, affected individuals may eventually have significant difficulty walking and require a wheelchair.

The specific symptoms and severity of Miyoshi myopathy vary greatly. The disorder is caused by mutations of a gene, dysferlin, that also causes limb-girdle muscular dystrophy type 2B (LGMD2B), a rare muscle disorder characterized by weakness of the proximal muscles of the of the hip and shoulder areas (limb-girdle area). Families have been reported in which some members develop Miyoshi myopathy and others LGMD2B. In addition, some patients with dysferlin mutations can have an anterior tibial distribution of weakness. (For more information on this disorder, choose "limb-girdle muscular dystrophy" as your search term in the Rare Disease Database.)

Distal Myopathy with Vocal Cord and Pharyngeal Signs (Distal Myopathy 2; MPD2)
This form of distal myopathy has only been described in one family. It is characterized by weakness and degeneration of the distal muscles of the hands and feet. In some cases, muscles of the shoulder area may become involved. Weakness of the vocal cord muscles and certain muscles of the throat (pharyngeal muscle) may also occur potentially resulting in difficulty swallowing (dysphagia) or the ingestion of food or liquids into the lungs (aspiration).

Distal Myopathy 3 (MPD3)
This extremely rare form of distal myopathy is characterized by muscle weakness and atrophy that can begin in the distal muscles of the arms or legs. Affected individuals may be clumsy with their hands or experience gait abnormalities (e.g., frequent stumbling). The disease will progress to affect additional muscles such as the proximal muscles of the upper legs. Mild contractures of the hands may be present. Onset has ranged from 32-45 years of age.

Causes

The distal myopathies are inherited as either autosomal dominant or recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Autosomal recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

The distal myopathies are caused by deficiency or lack of specific proteins that play an essential role in the proper function and health of muscle cells.

Laing distal myopathy is caused by mutations in the beta cardiac myosin (MYH7) gene located on the long arm (q) of chromosome 14 (14q12). The MYH7 gene contains instructions to create (encode) the muscle protein, myosin. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes (in most cases). Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 14q12" refers to a specific band on the long arm of chromosome 14. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Laing distal myopathy is inherited as an autosomal dominant trait.

Udd distal myopathy is caused by mutations of the titin (TTN) located on the long arm of chromosome 2 (2q24.3). The TTN gene encodes the muscle protein, titin, found in both skeletal and heart (cardiac) muscles. Udd distal myopathy is inherited as an autosomal dominant trait.

Inclusion body myopathy type 2 (DMRV) is caused by mutations of GNE gene located on the short arm of chromosome 9 (9p12-p11). The GNE gene encodes the protein UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. IBM2 is inherited as an autosomal recessive trait.

Miyoshi myopathy is caused by mutations of the dysferlin (DYSF) gene located on the short arm of chromosome 2 (2p13.3-p13.1). Miyoshi myopathy is inherited as an autosomal recessive trait.

Researchers have linked other forms of distal myopathy to specific chromosomes, but have not yet identified the causative genes. Welander distal myopathy has been linked to the short arm of chromosome 2 (2p13). Distal myopathy with vocal cord and pharyngeal signs has been linked to the long arm of chromosome 5 (5q). Distal myopathy 3 has been linked to the short or long arm of chromosome 8 (8p22-q12) or the long arm of chromosome 12 (12q13-q22). These three forms of distal myopathy are inherited as autosomal dominant traits.

Affected Populations

Since no distal myopathy has been linked to the X-chromosome, distal myopathies affect males and females in equal numbers. The exact incidence of the distal myopathies is unknown. Some forms have been identified with greater frequency in certain populations. Udd distal myopathy occurs with greater frequency in Finland where the prevalence is estimated to be 7 in 100,000 individuals. Welander distal myopathy occurs with greater frequency in Sweden where the prevalence is estimated to be 1 in 1,000 individuals. Approximately 220 cases of IBM2 have been identified in the medical literature. The muscular dystrophies as a whole are estimated to affect 250,000 individuals in the United States.

Related Disorders

Symptoms of the following disorders can be similar to those of distal myopathies. Comparisons may be useful for a differential diagnosis.

Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability.

Additional forms of muscle disease (myopathy) may be considered differential diagnoses for distal myopathy including metabolic myopathies such as Pompe disease; inflammatory myopathies such as dermatomyositis or polymyositis; and distinct congenital myopathies such as nemaline myopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Distal myopathies may also be mistaken for peripheral neuropathies, which can have a similar distribution of muscle weakness.

Standard Therapies

Diagnosis
A diagnosis of distal myopathy is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of tests including a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; magnetic resonance imaging (MRI) of muscle tissue; and surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers.

During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.

Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Elevated CK levels occur in some, but not all cases of distal myopathy, except for cases of Miyoshi myopathy where it is significantly elevated. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of distal myopathy.

MRIs of muscle tissue may reveal a distinct pattern of muscle damage or involvement. Distinct patterns have been identified in individuals with Welander, Udd and other distal myopathies.

Biopsy of affected muscle tissue may reveal characteristic changes such as increased connective tissue and fat. In some forms of distal myopathy, numerous sub-cellular compartments known as rimmed vacuoles can be detected on muscle biopsy.

Treatment
No cure exists for the distal myopathies. Treatment is aimed at the specific symptoms present in each individual. Specific treatment options may include physical and occupational therapy to improve muscle strength and, when necessary, the use of various devices including braces (e.g., ankle-foot orthosis) or wheelchairs to assist with walking (ambulation).

Genetic counseling may be of benefit for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: